2-Aryl-4-(1-[4-heteroaryl]piperazin-1-yl)methylimidazoles: dopamine . D.sub4 receptor subtype ligands

ABSTRACT

Disclosed are compounds of the formula: ##STR1## or the pharmaceutically acceptable acid addition salts thereof wherein: R a  represents ##STR2## where X, Y and Z are the same or different and represent CH or nitrogen; 
     R 1  R 2 , R 3  and R 4  independently represent organic or inorganic groups; and 
     R 5  is hydrogen, C 1  -C 6  alkyl or halogen, 
     which compounds are useful for the treatment and/or prevention of neuropsychological disorders including, but not limited to, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, Parkinson-like motor disorders and motion disorders related to the use of neuroleptic agents.

This application claims the benefit of U.S. Provisional Application No.60/098,834, filed Sep. 2, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to2-aryl-4-(1-[4-heteroaryl]piperazin-1-yl)methylimidazoles and topharmaceutical compositions containing such compounds. It also relatesto the use of such compounds in the treatment or prevention of psychoticdisorders such as schizophrenia and other central nervous systemdiseases.

2. Description of the Related Art

The therapeutic effect of conventional antipsychotics, known asneuroleptics, is generally believed to be exerted through blockade ofdopamine receptors. However, neuroleptics are frequently responsible forundesirable extrapyramidal side effects (EPS) and tardive dyskinesias,which are attributed to blockade of D₂ receptors in the striatal regionof the brain. The dopamine D₄ receptor subtype has recently beenidentified (Nature, 350: 610 (Van Tol et al., 1991); Nature, 347: 146(Sokoloff et al., 1990)). Its unique localization in limbic brain areasand its differential recognition of various antipsychotics indicatesthat the D₄ receptor plays a major role in the etiology ofschizophrenia. Selective D₄ antagonists are considered effectiveantipsychotics free from the neurological side effects displayed byconventional neuroleptics.

U.S. Pat. No. 5,428,164 describes piperidinylmethylphenyl-imidazolederivatives.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withdopamine subtypes. Accordingly, a broad embodiment of the invention isdirected to a compound of Formula I: ##STR3## or pharmaceuticallyacceptable addition salts thereof; wherein: R_(a) represents ##STR4##where X, Y and Z are the same or different and represent CH or nitrogen,provided that at least one of X, Y and Z is nitrogen;

R₁ R₂, R₃ and R₄ independently represent hydrogen, halogen, hydroxy, C₁-C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂ NH₂ ;

R₅ is hydrogen, C₁ -C₆ alkyl or halogen.

Dopamine D₄ receptors are concentrated in the limbic system (Science,265: 1034 (Taubes, 1994)) which controls cognition and emotion.Therefore, compounds that interact with these receptors are useful inthe treatment of cognitive disorders. Such disorders include cognitivedeficits which are a significant component of the negative symptoms(social withdrawal and unresponsiveness) of schizophrenia. Otherdisorders include those involving memory impairment or attention deficitdisorders.

Compounds of the present invention demonstrate high affinity andselectivity in binding to the D₄ receptor subtype. These compounds aretherefore useful in treatment of a variety of neuropsychologicaldisorders, such as, for example, schizophrenia, psychotic depression andmania. Other dopamine-mediated diseases such as Parkinsonism and tardivedyskinesias can also be treated directly or indirectly by modulation ofD₄ receptors.

Compounds of this invention are also useful in the treatment ofdepression, memory-impairment or Alzheimer's disease by modulation of D₄receptors since they exist selectively in areas known to control emotionand cognitive functions.

Thus, in another aspect, the invention provides methods for treatmentand/or prevention of neuropsychochological or affective disordersincluding, for example, schizophrenia, mania, dementia, depression,anxiety, compulsive behavior, substance abuse, memory impairment,cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonismand dystonia, and motion disorders related to the use of neurolepticagents. In addition, the compounds of the invention are useful intreatment of depression, memory-impairment or Alzheimer's disease.Further, the compounds of the present invention are useful for thetreatment of other disorders that respond to dopaminergic blockade,e.g., substance abuse and obsessive compulsive disorder. These compoundsare also useful in treating the extrapyramidal side effects associatedwith the use of conventional neuroleptic agents.

In yet another aspect, the invention provides pharmaceuticalcompositions comprising compounds of Formula I.

In another aspect, the invention provides intermediates useful in thepreparation of compounds of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

As mentioned above, the invention encompasses2-aryl-4-(1-[4-heteroaryl]piperazin-1-yl)methylimidazole derivatives ofFormula I.

Preferred compounds of Formula I are those where R₁ and R₂ are hydrogen,C₁ -C₆ alkyl, halogen, or hydroxy and R₃ is hydrogen. Other preferredcompounds of Formula I are those where R₃ is C₁ -C₆ alkyl in the 4position on the phenyl ring. Still other preferred compounds of FormulaI are those where R₁ and R₂ represent hydrogen, halgogen, C₁ -C₆ alkyl,or hydroxy, provided that one of R₁ and R₂ is hydrogen. Yet otherpreferred compounds of I are where R₅ is C₁ -C₆ alkyl.

Preferred compounds of Formula I are those where R_(a) is ##STR5## Suchcompounds are referred to hereinafter as compounds of Formula II. In thecompounds of Formula II, the definitions of X, Y, Z and R₄ are as setforth above for Formula I.

In preferred compounds of Formula II, X is nitrogen and Y and Z are CH.Such compounds are hereinafter referred to as compounds of Formula IIa.In other preferred compounds of II, X and Y are nitrogen and Z is CH(Formula IIb). In yet other preferred compounds of Formula II, X and Zare nitrogen and Y is CH (Formula IIc).

Other preferred compounds of Formula I are those where R_(a) is ##STR6##Such compounds are referred to hereinafter as compounds of Formula III.In the compounds of Formula III, the definitions of X, Y, Z and R₄ areas set forth above for Formula I.

In preferred compounds of Formula III, X is nitrogen and Y and Z are CH(Formula IIIa). In other preferred compounds of III, X and Y arenitrogen and Z is CH (Formula IIIb.). In yet other preferred compoundsof Formula III, X and Z are nitrogen and Y is CH (Formula IIIc).

Particularly preferred compounds of Formulas II and III (and of FormulasIIa-c and IIIa-c) are those where R₁ and R₂ are hydrogen, C₁ -C₆ alkyl,halogen, or hydroxy and R₃ is hydrogen.

Other particularly preferred compounds of Formulas II and III are thosewhere R₃ is 4-C₁ -C₆ alkyl.

Still other particularly preferred compounds of Formulas II and III arethose where R₁ and R₂ represent hydrogen, halgogen, C₁ -C₆ alkyl, orhydroxy, provided that one of R₁ and R₂ is hydrogen.

Yet other particularly preferred compounds of Formulas II and III arethose where R₅ is C₁ -C₆ alkyl.

The invention also provides intermediates useful in preparing compoundsof Formula I. These intermediates are represented by Formula IVa, IVb,and IVc. ##STR7##

In each of Formulae IVa, IVb, and IVc, R₄ carries the definition setforth above for Formula I.

In certain situations, the compounds of Formula I may contain one ormore asymmetric carbon atoms, so that the compounds can exist indifferent stereoisomeric forms. These compounds can be, for example,racemates or optically active forms. In these situations, the singleenantiomers, i.e., optically active forms, can be obtained by asymmetricsynthesis or by resolution of the racemates. Resolution of the racematescan be accomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table 1and their pharmaceutically acceptable acid addition salts. In addition,if the compound of the invention is obtained as an acid addition salt,the free base can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC-(CH₂)_(n) -COOH wheren is 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers. The invention includesall tautomeric forms of a compound.

By "C₁ -C₆ alkyl" or "lower alkyl" in the present invention is meantstraight or branched chain alkyl groups having 1-6 carbon atoms, suchas, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl,3-hexyl, and 3-methylpentyl. Preferred C₁ -C₆ alkyl groups are methyl,ethyl, propyl, butyl, cyclopropyl and cyclopropylmethyl.

By "C₁ -C₆ alkoxy" or "lower alkoxy" in the present invention is meantstraight or branched chain alkoxy groups having 1-6 carbon atoms, suchas, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy,hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By the term "halogen" in the present invention is meant fluorine,bromine, chlorine, and iodine.

Representative compounds of the invention are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                          #STR8##                                                                        -                                                                            #STR9##                                                                        -                                                                            #STR10##                                                                       -                                                                            #STR11##                                                                       -                                                                           ##STR12##                                                                    ______________________________________                                    

The invention also pertains to the use of compounds of general Formula Iin the treatment of neuropsychological disorders. The interaction ofcompounds of the invention with dopamine receptors is shown in theexamples. This interaction results in the pharmacological activity ofthese compounds.

The invention also pertains to the use of compounds of general Formula Iin the treatment of neuropsychological disorders. The interaction ofcompounds of the invention with dopamine receptors is shown in theexamples. This interaction results in the pharmacological activity ofthese compounds.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient;

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

A representative synthesis of the compounds of the invention ispresented in Scheme I. Those having skill in the art will recognize thatthe starting materials may be varied and additional steps employed toproduce compounds encompassed by the present invention. ##STR13##

In Scheme I, the definitions of R₁, R₂, R₃, R₄, R₅, X, Y and Z are asset forth above for Formula 1.

As shown, an azanaphthyl compound of general structure V, carrying anappropriate leaving group L, may be condensed with piperazine (VI) toprovide a 1-azanaphthyl piperazine of general structure IV. Compound IVmay then be condensed with a imidazole VII having an appropriate leavinggroup L₂ to provide a compound of Formula 1. The leaving groups L and L₂may be any suitable leaving group, e.g., a halide, a sulfonate ester, orthe like. Those having skill in the art will recognize that the startingmaterials may be varied and additional steps employed to producecompounds encompassed by the present invention.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE 1 Preparation of Intermediates

2,4-Dichloroquinazoline

A solution of 25 g of benzoyleneurea and 12 mL of diethyl aniline in 200mL of phosphorus oxychloride is refluxed for 4 days. Excess phosphorusoxychloride is removed on a rotovap and the remaining residue pouredonto ice. The mixture is extracted with ethyl acetate. The combinedorganic extracts are washed with water, 1 N NaOH solution, dried andconcentrated. The residue is recrystallized from isopropanol to provide11 g of the dichloroquinazoline as off-white needles (m.p. 118-121° C.).¹ H NMR (DMSO) 8.30 (d, J=7 Hz, 1H), 8.17 (ddd, J=7, 7, 1 Hz, 1H), 8.04(d, J=7 Hz, 1H), 7.90 (ddd, J=7, 7, 1 Hz, 1H).

2-Chloroquinazoline

A solution of 2,4-dichloroquinazoline (5 g) in methylene chloride (100mL) is combined with 100 mL of saturated brine containing 9% NH₄ OH andpowdered zinc (5 g). The resultant mixture is refluxed for 4 hours,cooled and filtered through celite. The organic layer is removed,diluted with ethyl acetate (100 ml), washed with 1 N HCl solution, driedand concentrated to yield 2-chloro-quinazoline.

1-Quinazolin-2-ylpiperazine

A solution of 2-chloroquinazoline (5 g) in 20 mL of toluene is addeddropwise to a refluxing solution of piperazine (20 g) in 150 mL oftoluene. The solution is heated for an additional 24 hours. Aftercooling to 0° C. for about 30 minutes, the solution is filtered. Thefiltrate is extracted with 10% acetic acid. The aqueous extracts arewashed with ether, basified and extracted with toluene. The toluenelayer is then washed with water, dried and concentrated. The resultingmaterial is placed under vacuum overnight to afford the title compound(6.8 g, m.p. 64-66° C.). ¹ H NMR (CDCl₃) 9.0 (s, 1H) , 7.66 (m, 2H),7.56 (d, J=8 Hz, 1H), 7.22 (ddd, J=8,7,1 Hz, 1H), 4.0 (t, J=5 Hz, 4H),3.05 (t, J=5 Hz, 4H).

EXAMPLE 2

2-{4-[(2-phenylimidazol-5-yl)methyl]piperazinyl}quinazoline

A sample of 2-phenyl-4-hydroxymethylimidazole (348 mg, 2 mmol) is heatedfor 5 min in thionyl chloride (5 mL) and subsequently concentrated.Chloroform (10 mL) is added and the solution reconcentrated. Theresulting dark oil is then taken up in chloroform (10 mL) and treatedwith 1-quinazolin-2-ylpiperazine (428 mg, 2 mmol) and triethyl amine (2mL). After 10 minutes, the reaction is washed with 2N NaOH solution,dried (Na₂ SO₄) and concentrated to provide the title compound (Compound4) as an oil (640 mg), the hydrochloride salt is prepared in aconventional manner, m.p. 101-105° C. (Compound 4a). ¹ H NMR (CDCl₃) 9.0(s, 1H), 7.9 (d, J=7 Hz, 2H), 7.65 (m, 2H), 7.55 (d, J=6 Hz, 1H),7.2-7.4 (m, 4H), 7.0 (s, 1H, imidazole CH), 3.95 (m, 4H), 3.6 (s, 2H),2.6 (t, J=5 Hz, 4H).

EXAMPLE 3

The following compounds are prepared essentially according to theprocedures set forth above in Examples 1 and 2.

(a) 2-(4-[{2-Phenylimidazol-5-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazoline (Compound 6).

(b) 2-(4-[{2-(4-Methylphenyl)imidazol-5-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazoline hydrochloride.

(c)2-(4-[{2-(3-Fluorophenyl)imidazol-5-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazolinehydrochloride.

(d)2-(4-[{2-Phenyl-5-methylimidazol-5-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazolinedimaleate.

(e)1-[(2-phenylimidazol-5-yl)methyl]-4-(2-5,6,7,8-tetrahydroquinolyl)piperazine(Compound 1).

(f)(1-[(2-phenylimidazol-5-yl)methyl]-4-(2-5,6,7,8-tetrahydroquinolyl)piperazinehydrobromide. (m.p. 270-275° C., Compound 1a).

(g) 1-[(2-phenylimidazol-5-yl)methyl]-4-(2-quinolyl)piperazine (Compound2).

(h) 1-[(2-phenylimidazol-5-yl)methyl]-4-(2-quinolyl)piperazinehydrobromide (m.p. 257-260° C., Compound 2a).

(i) 2-(4-[{2-Phenylimidazol-5-yl}methyl]piperazin-1-yl)-6-fluoroquinoline hydrobromide (m.p. 199-201° C.).

(j) 1-{[2-(2-fluorophenyl)imidazol-5-yl]methyl}-4-(2-quinolyl)piperazine(Compound 3).

(k) 1-{[2-(2-fluorophenyl)imidazol-5-yl]methyl}-4-(2-quinolyl)piperazineoxalate (m.p. 218-220° C., Compound 3a).

(l) 2-{4-[(2-phenylimidazol-5-yl)methyl]piperazinyl}quinoxaline (m.p.96-99° C., Compound 5).

EXAMPLE 4

Assays For D₂ And D₄ Receptor Binding Activity

The pharmaceutical utility of compounds of this invention is indicatedby the assays for dopamine receptor subtype affinity described below.

Pellets of COS cells containing recombinantly produced D₂ or D₄receptors from African Green monkey are used for the assays. A sample ishomogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer at 4° C.and pH 7.4 and then centrifuged at 30,000×g and resuspended andrehomogenized. The sample is again centrifuged at 30,000×g and the finaltissue sample is frozen until use. The tissue is resuspended 1:20(wt/vol) in 0.05 M Tris HCl buffer containing 100 mM NaCl.

Incubations are carried out at 48° C. and contain 0.4 ml of tissuesample, 0.5 nM ³ H-YM 09151-2(Nemonapride,cis-5-Chloro-2-methoxy-4-(methylamino)-N-(2-methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide)and the compound of interest in a total incubation of 1.0 ml.Nonspecific binding is defined as that binding found in the presence of1 mM spiperone; without further additions, nonspecific binding is lessthan 20% of total binding. The binding characteristics of representativecompounds of this invention for the D₂ and D₄ receptor subtypes areshown in Table 2 for rat striatal homogenates.

                  TABLE 2                                                         ______________________________________                                        Compound Number  D.sub.4 K.sub.i (nM)                                                                   D.sub.2 K.sub.i (nM)                                ______________________________________                                        1a               14       >1000                                                 2a 9  784                                                                     3a 17  978                                                                    4a 3 2676                                                                     5 8 2052                                                                    ______________________________________                                    

The binding constants of compounds of Formula I for the D₄ receptor,expressed in nM, generally range from about 0.5 nanomolar (nM) to about100 nanomolar (nM), and preferably less then about 25 nM. Thesecompounds typically have binding constants for the D₂ receptor of atleast about 500 nM. Thus, the compounds of the invention are generallyat least about 10 times more selective for the D₄ receptor than the D₂receptor. Preferably, these compounds are at least 20, and morepreferably at least 25-50, times more selective for the D₄ receptor thanthe D₂ receptor. Most preferably, these compounds are at least about 100times more selective for the D₄ receptor than the D₂ receptor.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compounds of the formula: ##STR14## orpharmaceutically acceptable addition salts thereof; wherein: R_(a)represents ##STR15## where X, Y and Z are the same or different andrepresent CH or nitrogen, provided that at least one of X, Y and Z isnitrogen;R₁ R₂, R₃ and R₄ independently represent hydrogen, halogen,hydroxy, C₁ -C₆ alkyl, trifluoromethyl, trifluoromethoxy or SO₂ NH₂ ;and R₅ is hydrogen, C₁ -C₆ alkyl or halogen.
 2. A compound according toclaim 1, wherein R_(a) is ##STR16##
 3. A compound according to claim 1,wherein R_(a) is
 4. A compound according to claim 2, wherein X isnitrogen and Y and Z are CH.
 5. A compound according to claim 2, whereinX and Y are nitrogen and Z is CH.
 6. A compound according to claim 2,wherein X and Z are nitrogen and Y is CH.
 7. A compound according toclaim 3, wherein X is nitrogen and Y and Z are CH.
 8. A compoundaccording to claim 3, wherein X and Y are nitrogen and Z is CH.
 9. Acompound according to claim 3, wherein X and Z are nitrogen and Y is CH.10. A compound according to claim 4, wherein R₁ and R₂ are hydrogen, C₁-C₆ alkyl, halogen, or hydroxy and R₃ is hydrogen.
 11. A compoundaccording to claim 4, wherein R₃ is 4-C₁ -C₆ alkyl.
 12. A compoundaccording to claim 4, where R₁ and R₂ represent hydrogen, halogen, C₁-C₆ alkyl, or hydroxy, provided that one of R₁ and R₂ is hydrogen.
 13. Acompound according to claim 12, where R₅ is C₁ -C₆ alkyl.
 14. A compoundaccording to claim 6, wherein R₁ and R₂ are hydrogen, C₁ -C₆ alkyl,halogen, or hydroxy and R₃ is hydrogen.
 15. A compound according toclaim 6, wherein R₃ is 4-C₁ -C₆ alkyl.
 16. A compound according to claim6, where R₁ and R₂ represent hydrogen, halogen, C₁ -C₆ alkyl, orhydroxy, provided that one of R₁ and R₂ is hydrogen.
 17. A compoundaccording to claim 16, where R₅ is C₁ -C₆ alkyl.
 18. A compoundaccording to claim 7 wherein R₁ and R₂ are hydrogen, C₁ -C₆ alkyl,halogen, or hydroxy and R₃ is hydrogen.
 19. A compound according toclaim 7, wherein R₃ is 4-C₁ -C₆ alkyl.
 20. A compound according to claim7, where R₁ and R₂ represent hydrogen, halogen, C₁ -C₆ alkyl, orhydroxy, provided that one of R₁ and R₂ is hydrogen.
 21. A compoundaccording to claim 20, where R₅ is C₁ -C₆ alkyl.
 22. A compoundaccording to claim 8, wherein R₁ and R₂ are hydrogen, C₁ -C₆ alkyl,halogen, or hydroxy and R₃ is hydrogen.
 23. A compound according toclaim 8, wherein R₃ is 4-C₁ -C₆ alkyl.
 24. A compound according to claim8, where R₁ and R₂ represent hydrogen, halogen, C₁ -C₆ alkyl, orhydroxy, provided that one of R₁ and R₂ is hydrogen.
 25. A compoundaccording to claim 24, where R₅ is C₁ -C₆ alkyl.
 26. A compoundaccording to claim 1, which is2-{4-[(2-phenylimidazol-5-yl)methyl]piperazinyl}quinazoline.
 27. Acompound according to claim 1, which is2-(4-{2-Phenylimidazol-5-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazoline.28. A compound according to claim 1, which is2-(4-[{2-(4-Methylphenyl)imidazol-5-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazolinehydrochloride.
 29. A compound according to claim 1, which is2-(4-[{2-(3-Fluorophenyl)imidazol-5-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazolinehydrochloride.
 30. A compound according to claim 1, which is2-(4-[{2-Phenyl-5-methylimidazol-4-yl}methyl]piperazin-1-yl)-5,6,7,8-tetrahydroquinazolinedimaleate.
 31. A compound according to claim 1, which is1-[(2-phenylimidazol-5-yl)methyl]-4-(2-5,6,7,8-tetrahydroquinolyl)piperazine.32. A compound according to claim 1, which is(1-[(2-phenylimidazol-5-yl)methyl]-4-(2-5,6,7,8-tetrahydroquinolyl)piperazinehydrobromide.
 33. A compound according to claim 1, which is1-[(2-phenylimidazol-5-yl)methyl]-4-(2-quinolyl)piperazine.
 34. Acompound according to claim 1, which is1-[(2-phenylimidazol-5-yl)methyl]-4-(2-quinolyl)piperazine hydrobromide.35. A compound according to claim 1, which is2-(4-[{2-Phenylimidazol-5-yl}methyl]piperazin-1-yl)-6-fluoroquinolinehydrobromide.
 36. A compound according to claim 1, which is1-{[2-(2-fluorophenyl)imidazol-5-yl]methyl}-4-(2-quinolyl)piperazine.37. A compound according to claim 1, which is1-{[2-(2-fluorophenyl)imidazol-5-yl]methyl}-4-(2-quinolyl)piperazineoxalate.
 38. A compound according to claim 1, which is2-{4-[(2-phenylimidazol-5-yl)methyl]piperazinyl}quinoxaline.